Meniscal tissue engineering: Bridging clinical needs and experimental innovation

Abstract

Meniscal injuries significantly impact knee function and pose clinical challenges globally. Conservative treatment and surgery are currently the more commonly used treatments, and there are still long-term joint problems such as incomplete meniscus healing and knee pain. Tissue engineering presents a promising alternative by using biomaterials, cellular therapies, and bioactive factors to repair meniscal damage. Despite the promising preclinical results, clinical applications still face challenges such as insufficient biomechanical strength, weak regenerative ability, or low durability. This review seeks to bridge clinical needs with engineering strategies by providing a comprehensive understanding of meniscal structure and function, as well as current treatments and their limitations. We aim to offer new insights to support the development of meniscus products in tissue engineering, thereby helping to lay a theoretical foundation for more accessible therapeutic solutions. Furthermore, we summarize recent advances in meniscus product research from both material and manufacturing perspectives within our laboratory.

The translational potential of this article

This review begins with an analysis of the macroscopic and microscopic structural characteristics of the meniscus, elucidating its critical physiological functions, thereby laying a theoretical foundation for the development of innovative meniscal repair strategy and providing structural design guidance for the construction of biomimetic meniscus. Subsequently, this review comprehensively summarizes the pathological characteristics of degenerative and traumatic tears, systematically evaluating the advantages and disadvantages of existing therapeutic approaches. Based on current clinical realities, it identifies treatment bottlenecks and unmet needs, offering reference points for research designs aligned with clinical requirements; addressing these problems specifically facilitates the translation of scientific findings into clinical products. Further, the review outlines the properties and manufacturing technologies of biomaterials, systematically comparing their performance in meeting the mechanical strength and functional demands of human meniscus, thus providing empirical references for material selection and fabrication techniques in next-generation product development. Finally, the review discusses the prospects and challenges of tissue engineering in meniscal therapy, aiming to enhance meniscal repair outcomes and provide personalized treatment protocols for patients with varying types of injuries.

Graphical abstract

Bridging the gap between clinical needs and experimental innovation can contribute to the flexible application of tissue engineering strategies for solving clinical problems. (Image source: Biorender).

1. Introduction

The meniscus plays an irreplaceable role in maintaining normal knee joint function, aiding in load transmission, stabilization, congruence and lubrication [1]. Meniscal injury is the second most common knee injury, with a prevalence ranging from 12% to 14% [2]. Meniscal injury often leads to knee pain and functional impairment, and may further result in severe joint pathology, including flattening of the joint surface, subchondral bone sclerosis, narrowing of the tibiofemoral joint space, cartilage degeneration, and the development and progression of knee osteoarthritis [3,4]. Therefore, meniscal repair is highly necessary.

Most patients with meniscal degeneration primarily undergo conservative treatment or partial meniscectomy [5]. For young patients with meniscus tears, the main treatment is meniscus repair surgery (such as, meniscal suture, meniscal replacement, and biological scaffold implantation) [[6], [7], [8]]. While surgical treatment involves substantial costs, early surgical intervention is strongly recommended for eligible patients [9,10]. Delayed treatment may lead to higher cumulative medical expenses, increased indirect costs, and potential need for more complex procedures [9,11]. Furthermore, meniscal tear type and technical factors (such as, inappropriate suture material, poor suturing technique, improper tension setting, and lack of surgical experience) may result in failure of meniscal repair [12]. Therefore, meniscal repair poses high demands from both economic and technical perspectives. There is an urgent need to develop effective treatment strategies applicable to different types of meniscal injury, as well as more convenient and economical repair systems.

Meniscal tissue engineering employs strategies such as cell therapy and biomaterial scaffolds to enhance tissue repair capacity, demonstrating significant potential in meniscal regeneration. Cells are vital in this process, aiding in matrix deposition and repair. Stem cells possess robust proliferative and differentiative capacities, making them widely utilized in meniscal repair [13,14]. The morphology and delivery method of cells to injury sites influence regeneration outcomes; direct injection can cause cell loss with synovial fluid, so scaffolds are used to support cell attachment, growth, differentiation, and extracellular matrix (ECM) deposition [14]. Advances in biomaterials (natural biomaterials, synthetic polymers, and composite constructs) and manufacturing (electrospinning, three-dimensional (3D) printing) technologies have made the fabrication of biomimetic meniscal scaffolds possible [[15], [16], [17]]. However, tissue engineering progress is mostly confined to the lab, with few products available for treating meniscal injuries.

This review systematically analyzes the structure and function of the meniscus, providing a structural reference for the fabrication of biomimetic meniscus scaffolds and serving as a reference for evaluating meniscus treatment outcomes. Considering individual patient differences, we further discuss the clinical classification and treatment strategies for meniscal injuries, identify unfavorable factors affecting healing, and highlight limitations of current therapeutic approaches. We then summarize the efforts of researchers in advancing meniscus injury repair. By systematically reviewing progress in clinical realities and laboratory research, we explore the prospects and challenges of translating laboratory findings into clinical applications. We hope to bridge the gap between clinical practice and laboratory research, leverage modern advanced technologies to generate scientific findings more aligned with clinical needs, enable targeted treatments for different injury types, achieve precision medicine, and ultimately help patients return to work, daily life, and sports in good health.

2. Structure and function of the meniscus

2.1. Meniscus structure

2.1.1. Macrostructure

The meniscus, composed of a uniquely geometric shape consisting of the medial meniscus (C-shaped) and the lateral meniscus (O-shaped), complements the morphological differences between the femoral condyles and the tibial plateau, thereby enhancing congruence in the tibiofemoral joint (Fig. 1a) [1,18]. The coverage rate of the medial meniscus over the medial tibial plateau in a healthy knee joint is approximately 45% to 60%, while that of the lateral meniscus is about 58% [18,21,22]. The appropriate coverage area of the meniscus contributes to the efficient transfer of forces and the uniform distribution of stress under load conditions [23]. The meniscus is firmly anchored to the tibia in a fan-shaped configuration via its anterior and posterior roots (Fig. 1b) [18]; Additionally, surrounding ligaments of the meniscus such as the transverse ligament, the meniscotibial ligaments, and the ligaments of Humphry and Wrisberg all contribute to joint stability, particularly rotational stability (Fig. 1b) [19,20,24,25].

Fig. 1.

Schematic diagram of the macroscopic and microscopic structure of the meniscus. (a) Meniscus macroscopic position and matching to femoral and tibial morphology [18]. (b) Important anatomical structures for maintaining meniscal stability: the root of the meniscus is attached to the tibia [18]; transverse ligament (anterior intermeniscal ligament) [19]; meniscotibial ligament [20]; Humphry ligament (the anterior meniscofemoral ligament) and Wrisberg ligament (the posterior meniscofemoral ligament) [19]. (c) Histological sections of the meniscus body [19], root (the meniscal horn bony insertion) [20], and the portion connected to the tibia [20]. MFC: medial femoral condyle, LFC: lateral femoral condyle, ACL: anterior cruciate ligament, PCL∗: posterior cruciate ligament, MM: medial meniscus, ML/LM: lateral meniscus, aMM: anterior root of medial meniscus, pMM: posterior root of medial meniscus, HL/AMFL: Humphry ligament (anterior menisco-femoral ligament), WL/PMFL: Wrisberg ligaments (posterior menisco-femoral ligament), TL/IL: transverse ligament (anterior intermeniscal ligament), MCL: medial collateral ligament, MTP: medial tibial plateau, ALMR: anterior lateral meniscal root.

2.1.2. Microstructure

The primary constituents of the knee meniscus are chondrocyte-like cells, fibroblast-like cells, as well as collagen fibers and proteoglycans (Fig. 1c) [2,8,19]. The meniscus contains predominantly parallel-aligned type I collagen fiber bundles in its outer region, which gives the meniscus the role of force transmission, shock absorption, and support in the knee joint [26,27]. The inner side is characterized by a unique collagen network composed of long-chain fibrous type II collagen, which has the capacity to adsorb various proteoglycan polymers, such as glycosaminoglycans [26,28]. The interwoven arrangement of collagen and proteoglycans enhances viscoelasticity and endows the meniscus with the capacity to resist tensile forces and withstand high compressive loads [27]. The circumferential fibers of the meniscus are arranged along their longitudinal edges, generating hoop stresses under load to uniformly distribute the load. The radial fibers distribute the stresses applied to the circumferential fibers and matrix of the meniscus, prevent transverse deformations, and distribute and reduce the contact pressures on the articular cartilage [29]. Current studies have quantified the overall compressive modulus of the meniscus under axial loading to range between 100 and 150 kPa [30]. Circumferential tensile modulus is estimated at approximately 100 to 300 MPa, and radial modulus is approximately 10 to 30 MPa [31,32]. The shear modulus of the meniscus is measured to be around 120 kPa [31]. The meniscus root gradually transitions into bone through a blend of non-calcified and calcified fibrocartilage, reducing stress concentration and risk of structural failure at the meniscus-bone interface; the meniscotibial ligament prevents lateral displacement of the meniscus (Fig. 1c) [20]. This transition also improves fatigue resistance under repeated loading, supporting the long-term mechanical function of the meniscus [[33], [34], [35]]. The current maximum load on the meniscal root is the anterior lateral (692 ± 304 N), followed by the posterior medial (678 ± 140 N), the posterior lateral (648 ± 200 N), and the anterior medial (407 ± 180 N) [36].

2.2. Meniscus function

2.2.1. Load transmission

The intact meniscus is capable of transmitting 70-99% of the total joint load [37]. The knee joint is highly loaded during daily life, with mean peak knee joint forces (% body weight, BW) ranking as follows: stair descent (346% BW) > stair ascent (316% BW) > level walking (261% BW) > single-leg stance (259% BW) > knee flexion (253% BW) > standing (246% BW) > sitting (225% BW) > bipedal standing (107% BW) [38]. The circumferential fibers of the meniscus facilitate the uniform distribution of load, thereby reducing cartilage pressure. The medial contact pressure in a knee following meniscectomy increases by 50-200% compared to a normal knee, and total meniscectomy can lead to approximately 4% annual loss of cartilage [39]. Loss of meniscal integrity from meniscus injury or total meniscectomy increased impact force by 113-121%, with the highest values observed after total meniscectomy [40].

2.2.2. Stability

The meniscus enhances static and dynamic stability of the knee joint mainly through morphologic congruity, firm root attachment, and support from surrounding ligaments (Fig. 1a–b). During movement, the meniscus is capable of anterior-posterior translation to adapt to changes in motion [41]. When the knee is flexed at an angle between 20° and 30°, the transverse ligament prevents the posterior translation of the anterior horn of the medial meniscus [24]. The meniscotibial ligament prevents extrusion and enhances the stability of tibial external rotation [25,42]. The Humphry and Wrisberg ligaments, whose tension is significantly correlated with posterior meniscal displacement, enhance the congruence between the posterior meniscal bow and the lateral femoral condyle while simultaneously withstanding both tensile and compressive forces [33,43]. Unilateral meniscectomy results in a 10% increase in knee laxity, while bilateral meniscectomy leads to a 20% increase [44]. Arno S et al. demonstrate that a medial meniscal root resection of ≥46% significantly alters the position and laxity of the medial femoral condyle [45]. A tear of the posterior root of the meniscus results in increased external rotation and lateral translation of the tibia [46]. Compagnoni R et al. indicated that a meniscal extrusion index (defined as the ratio of extruded width to total meniscal width) exceeding 20% may indicate pathological conditions that compromise the normal functional integrity of the meniscus [47].

2.2.3. Lubrication

The meniscus enhances joint lubrication by secreting lubricin. Preliminary reports indicate that lubricin exhibits differential affinities for various extracellular matrix components: highest affinity for fibronectin, moderate affinity for hyaluronic acid and type II collagen, and lowest affinity for type I collagen [48]. Immunohistochemical analysis reveals very strong lubricin immunostaining in normal meniscus, in contrast to weak/moderate staining seen in osteoarthritic meniscus [49,50]. The surface layer of lubricin coating torn edges of anterior cruciate ligaments and menisci may interfere with the integrative healing process needed for repair [51].

2.2.4. Proprioception

Proprioception governs the perception of limb and trunk position and movement, effort, squeeze, and heaviness [52]. The meniscus, particularly its root region, harbors various proprioceptive mechanoreceptors, including Pacinian corpuscles (rapidly adapting receptors), Ruffini endings (slowly adapting receptors), and Golgi tendon organs; these receptors regulate joint angle, movement speed, intra-articular pressure, and strain [53]. The ligamentous structure could contribute to stability of the knee by providing proprioceptive input, while preservation of the ligamentous structure might ensure a better functional outcome after surgery [54]. A decrease in proprioception adversely affects the activity of the quadriceps, balance, and strength, and increases the risk of new knee joint injuries [55]. Patients who underwent partial meniscectomy exhibit inferior proprioceptive functions, including knee joint position sense and muscle strength, compared to healthy joints, mainly at joint flexion angles of 60° and 75° [56,57]. Impaired proprioceptive accuracy is considered one of the contributing factors to knee pain or limited mobility, thereby facilitating the onset and progression of knee osteoarthritis [53].

2.3. Meniscal tissue engineering: lessons from structure and function

At the macroscopic level, meniscal tissue engineering scaffolds should match the anatomical shape of the femur and tibia, ensuring even load distribution and reducing stress concentrations. At the microscale, a gradient distribution of cells reflects tissue heterogeneity, while variations in fiber orientation represent biomechanical anisotropy. Tissue engineering scaffolds can be designed as stratified porous structures to promote the migration and aggregation of different cell types, thereby creating conditions for tissue regeneration and mimicking the native heterogeneity of the meniscus. Alternatively, when constructing meniscal scaffolds, attention may be focused on the anisotropic structure formed by the interweaving of circumferential and radial fiber networks. Designing scaffolds with a gradient modulus that matches the stress distribution of native tissue can provide a structural foundation for biomechanical restoration. Additionally, the stability, lubrication, and proprioceptive functions of meniscal implants should be considered. Partial replacements require secure fixation to native tissue, whereas total replacements require biomimetic attachment at the root insertion sites to ensure stability and function. Proper lubrication reduces joint friction, and restoration of proprioceptive function aids motor control, thereby enhancing recovery during daily and athletic activities.

3. Meniscal degeneration and tears: pathological characteristics and treatment

3.1. Pathological characteristics of meniscal degeneration

Meniscal degeneration refers to the microscopic structural alterations occurring without traumatic factors. Meniscal degeneration commonly occurs in middle-aged and elderly individuals and is typically triggered by metabolic imbalances within the meniscus, inadequate nutrient supply, or prolonged periods of excessive loading [58]. Microscopic structural alterations include changes in collagen fiber arrangement and composition, variations in proteoglycan (glycosaminoglycan) content, cellular hypertrophy and calcification, and aberrations in nerve and vascular structures [[59], [60], [61]]. The normal meniscus maintains balance through chondrocytes (Ch.1), regulating ECM synthesis and degradation to inhibit abnormal angiogenesis. During degeneration, this balance is disrupted, leading to neovascularization and elevated vascular permeability, which enables immune cells infiltration. Additionally, increased number of two other chondrocyte populations (Ch.2, associated with aberrant ECM degradation and remodeling; Ch.3, maintaining lubrication of the articular cartilage surface) recruit more immune cells. Their pro-inflammatory cytokines activate catabolic enzymes to further degrade the ECM, driving the tissue toward irreversible damage (Fig. 2a) [60]. A meniscus with a higher degree of degeneration is more likely to tear during a traumatic event [3]. Extensive infiltration of inflammatory factors inhibits meniscal tissue integration and meniscal cell migration in vitro, ultimately suppressing the repair process [60,70].

Fig. 2.

(a) Schematic illustration of microenvironment alterations caused by degeneration and meniscal tears [60,62]. Left image: changes in the microenvironment of normal and degenerated meniscus; right image: changes in the microenvironment associated with meniscal tears. (b) Schematic illustration of meniscal tear types [63]. (c) Schematic diagram of meniscus injury treatment. Conservative treatment: pharmacotherapy, intraarticular injections, physical therapy [64] (Image source: Biorender); surgical treatment: meniscectomy (Image source: Biorender), meniscal fixation [65], meniscal suturing [66], and allogeneic meniscus transplantation [67]. (d) All-inside hybrid repair systems commonly used in meniscal suturing (listed on the left) [66] and meniscal implants that have undergone clinical trials are used for partial or total meniscus replacement (listed on the right) [68,69]. PGA: poly(glycolic acid).

3.2. Pathological characteristics of meniscal tears

The meniscal tear refers to an aberration in the geometric configuration or anatomical position, which is commonly observed in young athletic populations. Meniscal tears are predominantly triggered by traumatic events, including sports-related injuries (such as basketball, football) or sudden external violence (such as motor vehicle accidents) [71]. Meniscal tears typically result in mechanical symptoms such as locking, catching, swelling, stiffness, and pain [72]. Meniscal tear types include horizontal, longitudinal, bucket-handle, radial, root, and complex tears (Fig. 2b) [63,71]. The horizontal tear is oriented parallel to the tibial plateau, dividing the meniscus into the superior and inferior leaflets [73]. Compared to the intact meniscus, horizontal tears result in a 14.2% increase in contact pressure and a 7.1% reduction in contact area [74]. The longitudinal tear is perpendicular to the tibial plateau, extending along the long axis of the meniscus, thereby dividing the meniscus into central and peripheral segments [75]. Longitudinal tears can extend to form bucket-handle tears, a condition commonly observed in young patients following trauma [76]. The radial tear is perpendicular to both the long axis of the tibial plateau and the meniscus, intersecting the longitudinal collagen bundles as they extend from the free edge toward the periphery [75]. Arthroscopic examination reveals that up to 25% of meniscal tears are of the radial type [7]. Radial tears compromise the circumferential integrity of the meniscus, leading to a precipitous loss of function and meniscal extrusion [77]. The meniscal root tear refers to a radial tear occurring within 1 cm of the meniscal root attachment or a complete avulsion of the meniscal root, potentially accompanied by osseous or ligamentous injuries. Anatomic reduction of a root avulsion plays a crucial role in delaying the onset of knee osteoarthritis and preventing the premature need for total knee arthroplasty [78]. Complex tears are a combination of longitudinal, radial, and horizontal tears [75]. Different types of meniscal tears can influence the intensity of pain. tears in the anterior and posterior horns of the meniscus correlate with higher Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores [79].

Following the meniscal tear, the knee joint microenvironment rapidly shifts toward a complex state dominated by inflammation, accompanied by mechanical abnormalities and metabolic imbalance. Studies simulating an acute meniscal tear have found that activated mononuclear leukocytes induce MMP activity, nitric oxide production, and loss of tissue sulfated glycosaminoglycan content [80]. Monocytes can further differentiate into macrophages and dendritic cells, and the pro-inflammatory cytokines released by macrophages may prolong the inflammatory response [62]. In patients younger than 40 years with a meniscal tear, significant expression of IL-1β, ADAMTS-5, MMP-1, MMP-9, MMP-13, and NFκB2 increases susceptibility to osteoarthritis [81]. Further histological analysis from animal experiments revealed synovitis one week after meniscal injury and knee joint pain sensitization eight weeks after injury [82]. The dual disruption of mechanobiology (such as altered loading, meniscus extrusion) and microenvironmental homeostasis (such as inflammation, catabolic enzymes) significantly impairs the migration, proliferation, and repair capability of meniscal cells, not only hindering intrinsic meniscal healing but also serving as a major driver of the onset and progression of post-traumatic osteoarthritis (Fig. 2a) [62].

3.3. Treatment of meniscal degeneration and tears

Meniscal degeneration, traumatic tears, and disruption of cellular microenvironment homeostasis compromise the meniscus's intrinsic healing capacity from both biological and biomechanical standpoints, while also promoting the onset and progression of knee osteoarthritis. Treatment options include conservative management, partial or total meniscectomy, and meniscal repair techniques like suturing, fixation, and transplantation (Fig. 2c). Degeneration is usually treated conservatively or with arthroscopic meniscectomy, while traumatic tears in younger patients often involve arthroscopic suturing. Although fixation devices like absorbable arrows and screws are easy to use, they often cause complications including cartilage damage, nerve irritation, synovitis, implant fracture, and subcutaneous migration; furthermore, a postoperative follow-up at 3 years revealed a failure rate exceeding 80%, which has led to a gradual decline in their clinical use [65,[83], [84], [85], [86], [87]]. Meniscus replacement is indicated for patients where suture repair is not feasible, injure results in meniscal loss, or persistent pain remains unalleviated [88,89].

3.3.1. Conservative treatment

Conservative treatment encompasses pharmacotherapy (oral nonsteroidal anti-inflammatory drugs), intraarticular injections, physical therapy, aimed at alleviating pain and enhancing knee joint functionality [64]. Nonsteroidal anti-inflammatory drugs are helpful for pain relief in acute injuries. Patients need to evaluate its side effects when using it, including gastrointestinal bleeding, renal dysfunction, and cardiovascular side effects (blood pressure, infarction, and fluid retention) [90]. Various intraarticular injections, including corticosteroids, hyaluronic acid, and orthobiologics (such as platelet-rich plasma), are available for clinical use. Corticosteroids can rapidly alleviate pain and inflammation associated with acute meniscal injuries; however, owing to their chondrotoxic effects and the risk of soft tissue atrophy, repeated corticosteroid injections should be used with caution [64]. Hyaluronic acid can promote joint lubrication, exhibiting anti-inflammatory effects [91]. Platelet-rich plasma can improve the catabolic environment of the meniscus [92]. Neither hyaluronic acid nor platelet-rich plasma can prevent the continued degeneration of the joint [93,94].

3.3.2. Surgical treatment

3.3.2.1. Meniscectomy

Numerous studies have demonstrated that while partial meniscectomy improves short-term functional outcomes, the resulting meniscal deficiency increases contact stress on articular cartilage [72,95]. The extent of meniscectomy significantly influences the contact stress between the tibia and femur, with larger resection areas resulting in greater contact stress [74]. Based on a follow-up period of 3.1 to 14 years after partial meniscectomy, the studies found that approximately 21.5% to 33% of patients exhibited joint space narrowing, osteophyte formation, malalignment, and even progression to knee osteoarthritis [72,88,95,96]. Katz JN and Sihvonen R et al. have identified that meniscectomy may elevate the risk of osteoarthritis or total knee arthroplasty by up to fivefold [97,98]. Meniscectomy is not an optimal treatment approach for meniscal injuries. Comprehensively considering, meniscal repair surgery is a more cost-effective preferred treatment.

3.3.2.2. Meniscus suture

Meniscal suture repair is currently the primary surgical technique in clinical practice. For a horizontal cleavage meniscal tear, using an all-inside repair technique to evenly compress the superior and inferior leaflets promotes meniscal healing [99]. Tachibana Y et al. reported that application of an all-inside repair technique for longitudinal meniscal tears resulted in complete healing of 48% of the torn sites [100]. All-inside repair of a bucket-handle meniscal tear achieves good reduction and stable fragment fixation [101]. Haklar U et al. employed an inside-out single or double vertical suture technique for the treatment of longitudinal medial meniscal tears, achieving a healing rate of up to 88.4% [28,102]. Radial tears are typically irreparable, firstly due to the difficulty in detecting minor tears and secondly because they often occur in avascular regions with limited nutrient supply [77,103,104]. Meniscal root tears are primarily treated through tibial tunnel suture repair and all-inside repair methods, which exhibit significantly superior clinical outcomes compared to conservative or resection approaches [105,106]. Complex meniscal tears are treated with flexible application of either suture techniques or meniscectomy [107].

Commonly used all-inside hybrid repair systems for meniscal suturing include the Fast-Fix (Smith & Nephew), Meniscal Cinch (Arthrex), Omnispan (DePuy Mitek), Max Fire (Biomet Sports Medicine), Sequent (ComMed) (Fig. 2d) [66]. The development of all-inside meniscal repair systems has relatively standardized the surgical procedure. However, precise control of surgical details (such as, knot placement and tension) still affects outcomes and demands a high level of technical expertise from the operator. Furthermore, the implant may irritate surrounding tissues, leading to complications such as cyst formation [12,66]. Von Essen C et al. conducted a cohort study and found that the failure rate of all-inside meniscal repair was 20.2% [108]. Ow ZGW et al. also found that the all-cause failure rate of traumatic meniscus repair increases over time after surgery [109]. Therefore, further investigation is required to explore more convenient and higher healing rate treatment methods for meniscus.

3.3.2.3. Meniscus replacements

Meniscal allograft transplantation effectively reconstructs knee biomechanics and protects cartilage by redistributing joint forces, but its source is precious and potential for immune rejection hinder widespread use [67,88,95]. Biomimetic scaffolds fabricated via tissue engineering demonstrate great potential in addressing challenges such as the limited availability of allografts and immune rejection reactions. Meniscal implants that have undergone clinical trials are used for partial or total meniscus replacement: the collagen meniscus implant (CMI), polycaprolactone-polyurethane-composed polyurethane polymer scaffolds (Actifit), poly(glycolic acid) (PGA)-based implant, ester-urethane (NUsurface), Artimis (Fig. 2d) [68,69].

Only Actifit and NUsurface are available in the market for sale. CMI have only obtained market access in certain countries. Degradable CMI, Actifit, and polyglycolic acid meniscal substitutes all offer short-term symptomatic relief for knee joints. The long-term outcomes of CMI and Actifit have been unsatisfactory [110,111]. Common complications of CMI include: limited regenerative, implant size reduction, lack of viscoelasticity, low stiffness, infection, synovitis, and migration [[112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123]]. The complications associated with Actifit and CMI are similar, with the additional occurrence of extrusion, cartilage degeneration, and bone bruises [115,118,120,121,[123], [124], [125], [126], [127], [128], [129]]. While the strength of polyglycolic acid stents has increased, the current observation period remains relatively short [69]. Non-degradable replacement materials for the meniscus, include NUsurface and Artimis. The NUsurface failure rate was 16.9% at 12 months [110,111]. The main concern with the NUsurface implant is the high rate of reoperation, associated risk of prolapse [130]. The Artimis meniscus prosthesis, designed from MR images of 35 healthy menisci, includes anterior and posterior horns for tibial fixation, yet may cause device-related issues, pain, and motion deficits [[131], [132], [133]]. MenisciKnit, with a microstructure mimicking natural tissue, optimizes stress distribution but is still in early clinical trials and used in few countries [7].

3.4. Meniscal tissue engineering: lessons from pathological characteristics and treatment

Table 1 provides a further intuitive overview of the advantages and disadvantages of surgical treatment based on the preceding content. Based on the advantages and disadvantages of each treatment, inspirations for future directions in tissue engineering development include: (1) Meniscal suture repair systems: technical improvements should aim to reduce process complexity and shorten the learning curve for physicians, and create new suture materials or fixation methods to enhance healing rates and prevent cyst formation; (2) Meniscal replacement implants: a balance must be achieved between material degradation rate and tissue regeneration capability; particular attention should be given to the biomechanical properties and durability of regenerated tissue, as well as reliable implant fixation. Furthermore, the regulation of the microenvironmental homeostasis in the knee joint should be emphasized to promote meniscus healing.

Table 1.

Advantages and disadvantages of clinical application strategies.

Device	Clinical data∗ (year)	Advantages	Disadvantage
Meniscal suture [12,108,[134], [135], [136], [137]]	>10	Suture securely; Most frequently used; Optimal biomechanics	High technical complexity; Cyst formation; Poor healing; Failure (20.2%)
Meniscal fixation [65,[83], [84], [85], [86], [87]]	>5	Absorbable arrows/screws; User-friendly; Operation; Shorter surgical time	Cartilage injures; Synovitis; Neural stimulation; Fixed low intensity; Implant fracture; Subcutaneous migration; Failure (>80%, after 3 year)
CMI [[112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123]]	>10	Regeneration	Limited regenerative; Implant size reduction; Lack of viscoelasticity; Low stiffness; Infection; Synovitis; Migration; Failure (36%)
Actifit [115,118,120,121,[123], [124], [125], [126], [127], [128], [129]]	>10	Regeneration	Infection; Limited regenerative; Lack of viscoelasticity; Low stiffness; Extrusion; Migration bone bruises; Cartilage degeneration; Failure (6.3-31.8%)
PGA-based implant [69]	1	Regeneration; Biomechanics (shear forces)	Short follow-up; Migration; Limited regenerative
NUSurface [118,121,130,138]	1	Permanent replacement	No fixation; Extrusion; Reoperation (37%); Replacement (21%)
Artimis [[131], [132], [133]]	<1	Permanent replacement	Persistent pain; Fixed failure; Device related adverse events; Range of motion deficit

CMI: Collagen meniscus implant, PGA: poly(glutamic acid).

4. Laboratory advances in meniscus tissue engineering

Cell therapy is a key component of meniscus tissue engineering strategy. The stem cells commonly used for meniscus repair mainly originate from mesenchymal stem cells (MSCs) in bone marrow, adipose tissue, and synovium (Fig. 3a). Stem cells possess excellent potential for fibrocartilage differentiation and immunomodulatory functions (by secreting cytokines and exosomes to regulate the local inflammatory microenvironment, thereby promoting tissue repair and integration) [14]. Pure cell therapy enables the regenerated area of meniscal defects to approach that of the native meniscus; however, it lacks effective structural support, and the biomechanical strength of the regenerated tissue remains unknown (Fig. 3a) [[139], [140], [141]]. Scaffolds serve as the cornerstone of tissue engineering, providing a platform for cell adhesion and growth. The materials commonly used for hydrogel or scaffolds include natural polymers, as well as absorbable and non-absorbable synthetic polymers; outcome are often reflected in their structural support, biocompatibility, regenerative capacity, and biomechanical stability (Fig. 3b). With the advancement of manufacturing technologies such as electrospinning and 3D printing, their advantages in tissue engineering applications are evident (Fig. 3b), facilitating the realization of biomimetic native meniscus structures across macro-to micro-scales while enhancing mechanical strength [142,143].

Fig. 3.

(a) Illustrated common stem cell types, their usage (Image source: Biorender), and results from animal experiments [[139], [140], [141]]. (b) Lists commonly used natural polymers as well as absorbable and non-absorbable synthetic polymers; frequently used as hydrogels and scaffolds; outcome are often reflected in their structural support, biocompatibility, regenerative capacity, and biomechanical stability. (c) Provide examples of the advantages of two manufacturing technologies: electrospinning and three-dimensional printing [142,143]. MSCs: mesenchymal stem cells, DECM: decellularized extracellular mat matrix, DMECM: decellularized meniscus extracellular matrix, PCL: polycaprolactone.

4.1. Cellular therapy

MSCs can differentiate into fibrocartilaginous tissue resembling the meniscus and further enhance the production of extracellular matrix, thereby promoting the integration of regenerated meniscal tissue with host tissues [144]. MSCs exhibit low immunogenicity, along with favorable differentiation potential and cartilage repair capabilities. Bone marrow mesenchymal stem cells (BMSCs) were the first to be employed in regenerative medicine, demonstrating high usage rates and extensive research coverage, yet they carry a risk of hypertrophic differentiation. Adipose-derived mesenchymal stem cells (ADSCs) are the most accessible and abundant, with strong proliferative capacity but relatively poor phenotypic stability. Synovium-derived mesenchymal stem cells (SMSCs) closely resemble meniscal cells in terms of gene expression and possess the greatest potential to generate fibrochondrocytes, making them the most promising stem cells for meniscal tissue engineering [14,144].

Stem cell therapy without scaffolds involves injecting or culturing stem cells into aggregates for implantation into damaged meniscus sites. Hatsushika D et al. used SMSCs from porcine synovium in a meniscus defect model, injecting 5 × 10⁷ allogeneic cells at weeks 0, 2, and 4 [139]. By week 16, regenerated tissue showed significant type I and II collagen presence, with MRI T2 values similar to native tissue, indicating strong regeneration. The study highlights the need to balance injection frequency for optimal efficacy and safety, as too few injections reduce effectiveness while too many risk synovitis, unwanted tissue growth, and tumorigenesis. Takata Y et al. cultured MSCs from rabbit inter-scapular adipose tissue into cell sheets and implanted them in a rabbit model with a meniscus defect [140]. At 12 weeks, the ADSC sheets showed strong regenerative capacity, with the regenerated area nearly matching the native meniscus. However, the long-term evolution of these ADSC sheets is still uncertain. Kondo S et al. isolated SMSCs from primates and after culturing them into cell aggregates, reimplanted the aggregates into meniscal defect models in the same animals [141]. The resulting regenerated tissue area approached that of the native meniscus and effectively prevented cartilage degeneration, underscoring the substantial potential of SMSCs for meniscal repair. Autologous SMSCs may provide safer and more desirable therapeutic outcomes than allogeneic SMSCs, but they are more costly and time-consuming to prepare.

While these studies show promise for stem cells in meniscal regeneration, none have assessed mechanical tests on the regenerated tissue, and the observation periods were too short to verify long-term tissue functionality. The method of stem cell delivery, as well as the ability and duration of cell retention at the injury site, can influence meniscal regeneration capacity. Whether the regenerated tissue recapitulates the highly organized circumferential and radial collagen network of the native meniscus, remains unexplored. Nevertheless, ongoing advances in tissue engineering may address this shortcoming. Modern fabrication techniques allow the creation of scaffolds with native-like fiber orientation, providing cell attachment sites, improving mechanical strength, and modulating the microenvironment to support cell survival. The combined strategy of cells and scaffolds offers substantial potential for achieving functional parity with the native meniscus.

4.2. Material selection

4.2.1. Natural polymers

Natural polymers such as collagen, decellularized extracellular matrix (DECM), and silk fibroin are used in meniscal repair hydrogels and scaffolds, where their porous structure facilitates nutrient exchange and their good biocompatibility promotes tissue regeneration [[145], [146], [147], [148], [149], [150], [151]]. Pan Z et al. combined intra-articular gefitinib (modulating EGFR signaling to promote regeneration) delivery with a customized multilayer collagen scaffold for meniscal defect repair, increasing the deposition of extracellular matrix (Fig. 4a) [149]. Silk fibroin scaffolds demonstrated compressive properties comparable to native meniscus six months after implantation (Fig. 4b) [147]. Decellularized meniscus extracellular matrix (DMECM) improves porosity through freeze-thaw methods, enhancing cartilage formation and increasing type I collagen expression [148,152]. DMECM hydrogel with BMSCs shows excellent fibrochondrogenic regeneration in rat meniscal defects, aiding tissue repair and preventing osteoarthritis (Fig. 4c) [148]. Bacterial cellulose gel is cost-effective, malleable, and has a better compressive modulus than collagen implants, but lacks detailed material characterization and animal testing [153]. However, the animal experiment results shown in Fig. 4a–b indicate that the scaffold morphology did not adequately match the native meniscus, and the regenerated tissue remained notably different from the native meniscus. The inherent low stiffness and limited regenerative capacity of natural polymer scaffolds cannot guarantee long-term efficacy in inhibiting cartilage degeneration [145,152,154,155]. The combination of natural polymers with biological factors and stem cells can further enhance their regenerative capacity [14,148,149,156]. Current studies lack an assessment of the mechanical properties of regenerated tissue. Instability of meniscal scaffold fixation can lead to poor integration between the scaffold edges and surrounding tissues. Thus, when using natural polymers to fabricate meniscal repair products, we might consider designing them as smart delivery platforms for biological factors, drugs, or stem cells, and in an injectable form. Injectable products are suitable for meniscus degeneration, minor tears, or as an adjunct to promote healing after suturing. At the same time, this approach aligns with the current trend toward minimally invasive treatment.

Fig. 4.

(a) Schematic diagram of the collagen scaffold fabrication and the results of animal experiments. The solid line area represents the normal meniscal region, while the dashed line area indicates the regenerated meniscal region [149]. (b) Schematic diagram of silk fibroin scaffold fabrication and results of animal experiments [147]. (c) Schematic diagram of the decellularized extracellular matrix hydrogel fabrication and the results of animal experiments [148]. BMSCs: bone marrow mesenchymal stem cells.

4.2.2. Biodegradable polymers

Biodegradable polymers commonly include poly(glutamic acid) (PGA), poly(lactic acid) (PLA), and polycaprolactone (PCL). The biodegradable polymer offers superior structural and biomechanical stability compared to natural polymers, yet its treatment exhibits diminished tissue regenerative capacity and biocompatibility relative to cell therapy and natural polymer treatment [15,[157], [158], [159], [160], [161], [162], [163], [164], [165], [166], [167], [168], [169]]. Tissue engineering commonly employs composite strategies combining natural polymers, synthetic polymers, cells, and bioactive factors to address repair challenges. The blend of natural and synthetic polymers enhances the strength of regenerated tissue and provides early structural support [168].

The fibrin/polyethylene oxide (Fb/PEO) hydrogel exhibits a semi-interpenetrating polymer network structure, with the compressive modulus of the scaffold increasing from an initial 120.1 ± 3.3 kPa to 4.05 ± 0.61 MPa after 12 weeks of in vivo implantation, demonstrating excellent tissue regeneration capability (Fig. 5a) [159]. The effective structural support provided by the PEO scaffold promotes the regenerative capacity of hydrogels. The PLGA-g-PCL hydrogel, after extensive crosslinking, shows improved elasticity with a compressive strength over 0.60 MPa and a strain of about 70%, surpassing the PLGA hydrogel; however, the regenerative capacity of the hydrogel is relatively weak in the absence of adipose-derived stem cells (Fig. 5b) [170]. The compressive resistance and regenerative capacity of the Fb/PEO hydrogel were significantly higher than those of PLGA-g-PCL hydrogel. Murakami T et al. used poly(L-lactic acid) sponge, PGA-coated poly(L-lactic acid) sponge, PGA lamination, and film-coated PGA lamination effectively to cover circular defects in the rabbit meniscus (Fig. 5c) [162]. Film-coated PGA lamination exhibited the best compressive resistance, good regeneration and less inflammation. Otsuki S et al. found that meniscal scaffold prepared from PGA coated with poly(lactic acid/caprolactone), has low compressive stress and elastic modulus; but at 24 weeks, the scaffold is replaced by newly generated collagen, and the defect is covered (Fig. 5d) [166]. As shown in Fig. 5, the combined tissue engineering strategies largely restored the meniscal defect area in animals. However, due to the lack of comprehensive mechanical testing of the regenerated tissue, it is impossible to determine whether it can adequately fulfill the physiological functions of the meniscus. We have summarized the biomechanical strength of these hydrogels or scaffolds in Table 2. Compared with the standard mechanical properties of the human meniscus (circumferential tensile modulus: 100 - 300 MPa; radial tensile modulus: 10 - 30 MPa; compressive modulus: 100 - 150 kPa), only the compressive performance could be matched. Currently, complete replication of the native meniscus biomechanical properties remains unattainable. The combination strategies described may be more suitable for meniscal injury with partial defects, but the specific area of defect to which they are applicable requires further investigation. For partial meniscal defects, hydrogel injection is more convenient than suturing or scaffold implantation. Meanwhile, it faces the challenge of underwater gelation, as meniscal repair surgery is typically performed arthroscopically in clinical practice.

Fig. 5.

(a) The fabrication of Fb/PEO hydrogel and the results of animal experiments [159]. (b) The fabrication of PLGA-g-PCL hydrogel and the results of animal experiments [170]. (c) Comparison of biomechanical strength of s-PLLA, p-PLLA, l-PGA, and f-PGA and the results of animal experiments [162]; the image of the punch model is sourced from Biorender. (d) The fabrication of meniscal scaffold (prepared from PGA coated with P(LA/CL) and results of animal experiments [166]. Fb/PEO: fibrin/polyethylene oxide, PCL: polycaprolactone, PLGA: poly(L-glutamic acid), ASCs: adipose‐derived stem cells, s-PLLA: poly(L-lactic acid) sponge, p-PLLA: polyglycolic acid-coated poly(L-lactic acid) sponge, l-PGA: polyglycolic acid lamination, f-PGA: film-coated polyglycolic acid lamination, PGA: poly(glycolic acid), P(LA/CL): poly(lactic acid/caprolactone).

Table 2.

Summary of laboratory application strategies.

Strategies	Material	Type	Outcome	Advantage	Disadvantage	Biomechanical
Natural Polymers [[145], [146], [147],153,154,171,172]	Collagen	Hydrogel; Scaffold; Membrane	Regeneration; Structural support; Biocompatibility; Biomechanical; Stability	Porous structure; High elasticity; Clinical application	Insufficient mechanical strength	CM (CMI): 13 ± 5 kPa [172]
	DECM; DMECM			Enhancement of porosity		TM: 0.10 ± 0.04 MPa [171] CM: 0.21 ± 0.03 MPa [171]
	SF			Porous structure; High elasticity; Better compression performance		CM: 1.1 ± 0.2 MPa [147] CM: 3.3 ± 0.5 MPa [154]
	Bacterial cellulose	Hydrogel	Regeneration; Biomechanical; Stability	Organic polysaccharides; Low cost; Better compression performance	Lack of detailed material characterization, animal experimentation	TM: 1 MPa [153]
Resorbable synthetic polymers [[157], [158], [159],162,164,[166], [167], [168], [169], [170]]	PCL	Scaffold; Hydrogel	Structural support; Biocompatibility; Regeneration; Biomechanical stability	Slow degradation rate	Insufficient regenerative capacity	The biomechanical strength may vary depending on its manufacturing process. For example: TM (PCL, 3D printing): 30.59 ± 1.93 MPa [158] CM (PCL, 3D printing): 22.48 ± 1.04 MPa [158]
	PLA	Scaffold; Hydrogel		Moderate degradation rate
	PGA	Scaffold; Hydrogel		Rapid degradation rate
	Fb PEO	Hydrogel	Segmental meniscal defect regeneration; Regeneration area: Fb/PEO hydrogel > Fb hydrogel	Slower biodegradation; Structural support promotes regeneration; Regenerated tissue: better compression performance	Lack of testing for tensile properties; Differences in the mechanical properties between humans and rabbits.	Hydrogel CM: 120.1 ± 3.3 kPa [159] Regenerated tissue CM: 4.05 ± 0.61 MPa [159] Rabbit CM: 6.57 ± 1.66 MPa [159]
	PLGA PCL	Hydrogel	Segmental meniscal defect regeneration	Better elasticity; Porous structure; Adjusted to perform a load-bearing function and support tissue regeneration	Lack of more detailed mechanical properties testing.	Greater than 0.60 MPa with a maximum strain of about 70% [170]
Resorbable synthetic polymers [[157], [158], [159],162,164,[166], [167], [168], [169], [170]]	PLLA PGA	Scaffold	Cylindrical meniscal defect regeneration	Layering and stacking enhance mechanical properties	Synovial hyperplasia	Compression force at 50%, maximum CM:53.44 MPa [162]
	PGA P(LA/CL)	Scaffold	Segmental meniscal defect regeneration;	Slower biodegradation; Customizability	The tensile modulus and compressive modulus are significantly lower than those of the porcine meniscus	Maximum radial force was almost 15 Mpa [166]
	Collagen HA P(DTDDD)	Scaffold	Replacement native menisci: ultimate tensile load: 572.6 ± 210.9 N [166] tensile stiffness: 143.5 ± 41.6 N/mm [167]	Time-zero scaffolds: ultimate tensile load: 524.6 ± 48.6 N tensile stiffness: 249.4 ± 34.1 N/mm CM: 0.15 MPa [168]; Comparable to a natural meniscus	Altitude loss; Extrusion; Scar formation; Regenerated tissue: body becomes narrow, strength decreases	Regenerated tissue: ultimate tensile load: 210.4 ± 14.0 N [167] tensile stiffness: 66.1 ± 32.5 N/mm [167] CM: 0.33 MPa [168]
	PCL SMSCs	Scaffold; Electrosp-inning technolo-gy/TEC	Segmental meniscal defect regeneration; Fiber-oriented circular fibers	Adjustable nanofiber orientation; PCL: structural support, TEC: attracts cell adhesion, regeneration	The standalone stent group exhibited no tissue coverage	TM (PCL scaffold): 10–15 MPa [157] TM (SMSCs TEC): 1.2 MPa [157]
Resorbable synthetic polymers [[157], [158], [159],162,164,[166], [167], [168], [169], [170]]	PCL DMECM	Scaffold; Electrospi-nning technolog-y	Replacement Repair of the meniscal circumferential structure	Adjustable nanofiber orientation; Customizability; anti-suture properties; Porous structure; Meniscus covering the tibial plateau area: 70.2 ± 3.7%; Scaffold covering the tibial plateau area: 61.8 ± 7.5% (6-month)	Inadequacy in mechanical properties	TM (oriented): 8.5 ± 1.9 MPa [171] TM (horizontal): 2.3 ± 0.3 MPa [171] CM: 0.21 ± 0.03 MPa [171]
	PVA DMECM	Scaffold	Cylindrical meniscal defect regeneration; Area of meniscal repair:92%	3D printing technology; Bionic structures; Pore structure; Biomechanical enhancement	Mechanical properties remain inadequate; Long-term efficacy remains uncertain	20 - 40% compression: 0.49 MPa [164]
	PCL DMECM GelMA	Scaffold	Cylindrical meniscal defect regeneration			TM [158]: 24.86 ± 0.43 MPa CM: 12.63 ± 2.10 MPa
	PCL/Fib	Scaffold	Replacement			TM: 61.45 ± 11.75 MPa [169] CM: 42.25 ± 5.47 MPa [169]
Non-resorbable synthetic polymer [[173], [174], [175], [176], [177], [178], [179], [180], [181], [182]]	Teflon	Permanent Implants	Structural support; Biomechanical; Stability	Low friction	Extrusion; Inflammation; Poor machinability;	-
	PET			Wrinkle resistance; Abrasion resistance	Low rigidity precludes; Limited chondroprotective capacity; Synovitis	-
	PVA-H			Synthetic simplicity; Biocompatibility; Highwater content; High elasticity	Insufficient mechanical properties; Limited chondroprotective capacity	Viscoelastic behavior similar to that of human meniscus [179]
	PU			Wear resistance; Applied in clinical settings; Excellent viscoelastic properties; Biological stability; Biocompatibility	Extrusion; Insufficient mechanical properties	CM: 19.62 MPa [181]

DECM: decellularized extracellular matrix, DMECM: decellularized meniscus extracellular matrix, SF: silk fibroin, PCL: polycaprolactone, PLA: poly(lactic acid), PGA: poly(glutamic acid), Fib/Fb: fibrin, PEO: polyethylene oxide, PLLA: poly-l-lactic acid, PLGA: poly(L-glutamic acid), P(LA/CL): poly(lactic acid/caprolactone), P(DTDDD): poly (desaminotyrosyl-tyrosine dodecyl ester dodecanoate), SMSCs: synovium‐derived mesenchymal stem cells, GelMA: gelatin methacrylate, PET: poly(ethylene terephthalate), PVA-H: poly(vinyl alcohol) hydrogel, PU: poly(carbonate urethane), TEC: tissue-engineered construct, 3D: three-dimensional, TM: tensile modulus, CM: compression modulus.

Further, balancing the relationship between tissue regeneration and scaffolds degradation is critical. Material selection and manufacturing processes are critical to the success or failure of the outcome. Patel JM et al. created a meniscus replacement using a collagen-hyaluronan sponge with degradable poly(desaminotyrosyl-tyrosine dodecyl ester dodecanoate) (P(DTDDD)) fibers to mimic meniscus structure [167]. Initially, these scaffolds had similar tensile load and higher stiffness than native meniscus. After 52 weeks, the implant's tensile load was about one-third, and its stiffness was about half that of a natural meniscus. A PLLA fiber-reinforced collagen-hyaluronan scaffold implanted in sheep for 32 weeks showed significant narrowing and reduced mechanical properties, except for a slight increase in permeability [165]. Both meniscal implants initially matched human tissue strength but weakened due to degradation, with PLLA being less durable than P(DTDDD). Therefore, when fabricating total meniscal replacement scaffolds, in addition to ensuring biomechanical matching, we must select biomaterials that degrade slowly and promote regeneration, aiming to achieve in situ regeneration and transform the scaffold into a “living scaffold”. The development of 3D printing technology has brought us one step closer to this goal. Researchers have used “bio-inks” to mimic the structure of the native meniscus. As shown in Table 2, Table 3D printing led to a marked improvement in biomechanical properties.

Table 3.

Three-dimensional printing process.

Printing	Strategies	Operational methodology	Characteristics	Ink
Nozzle-based printing method	Inkjet printing	The process is one that constructs three-dimensional objects by jetting micro-droplets of photopolymer or support materials from a printhead on demand, followed by layer-by-layer curing and stacking.	Adaptation to low ink viscosity; Flexible printhead replacement; Customizable tissue fabrication in various shapes and sizes; Prone to clogging	Low-Viscosity Biopolymers
	Micro-extrusion printing	Bioink is used to fabricate three-dimensional structures through the continuous extrusion of filamentous, viscous fluid material, via a precision-controlled micro-nozzle under relatively low pressure. The material is deposited layer by layer onto a build platform, where it undergoes self-curing via mechanisms such as cooling, cross-linking reactions, or solvent evaporation.	Adapted for high-viscosity and high-strength materials; expanding the scope of applications; Customized fabrication of tissues in various shapes and sizes	Various Biopolymers
Nozzle-less 3D printing	LAB SLA DLP Volumetric	This process employs light, heat, electric fields, acoustic waves, or other physical fields in place of mechanical nozzles to achieve precise material shaping and solidification.	High resolution and precision; Reduction in contamination risks; Elimination of constraints imposed by nozzle diameter, ink viscosity, and linear motion; High equipment costs	Photocurable polymers; Biomaterials

LAB: laser-assisted bioprinting, SLA: stereolithography, DLP: digital light processing.

4.2.3. Non-absorbable polymers

Non-absorbable polymers include Teflon, poly(ethylene terephthalate) (PET), poly(vinyl alcohol) hydrogel (PVA-H), and polyurethane. Teflon, characterized by its high molecular weight and hydrophobic properties, nevertheless poses risks associated with lateral extrusion and inflammation [173,174]. PET exhibits remarkable wrinkle resistance and abrasion resistance. Its low rigidity precludes its ability to safeguard cartilage, instead exacerbating synovitis and chronic synovitis [173,175]. PVA-H possesses a simple structure and is easy to synthesize, and while it exhibits excellent biocompatibility, high water content, and elasticity surpassing that of the natural meniscus, its mechanical properties are insufficient to prevent continued cartilage degradation [[176], [177], [178], [179]]. Polyurethane exhibits excellent abrasion resistance and good biocompatibility, making them widely utilized in orthopedic applications. The progression of injure in the autograft group for degenerative changes in cartilage is similar, but it is important to note that brittle fracture, plastic deformation, and fixation failure should be carefully monitored [[180], [181], [182]].

4.3. Design and manufacturing

4.3.1. Tissue-engineered construct

To furnish a three-dimensional environment with enhanced mechanical properties conducive to cellular survival and mitigate the risks associated with xenogenic materials, a scaffold-free tissue-engineered construct (TEC) derived from SMSCs has been developed [183,184]. The capacity of allogeneic SMSCs treated with TEC for repairing meniscal defects is significantly twice that of the control group. The TEC-treated defects were consistently repaired by a fibro-cartilaginous tissue with good tissue integration to the adjacent host meniscal tissue, while the untreated were either partially or not repaired (Fig. 6a) [183]. ADSCs treated with TEC exhibited gradually increasing levels of COL2 and SOX9, surpassing those of the control group starting from week four [185]. Additionally, there was a notable enhancement in contact area, elastic modulus, and ultimate tensile strength, accompanied by a reduction in peak pressure [186]. However, the biomechanical strength of the repaired meniscus remains significantly lower than that of the native meniscus. Combining electrospinning and other techniques may simultaneously enhance both the strength and regenerative capacity of the scaffold.

Fig. 6.

(a) Repair of meniscal lesions using a scaffold-free TEC derived from allogenic SMSCs in a miniature swine model [183]. (b) The fabrication of the composite scaffold (two layers of two layers of DMECM sponge and three layers of electrospinning DMECM/PCL fiber films) and the results of animal experiments [171]. (c) The fabrication of the composite scaffold (an aligned electrospun nanofibrous scaffold combined with a TEC derived from SMSCs) and the results of animal experiments [157]. TEC: tissue-engineered construct, PCL: polycaprolactone, ECM: extracellular matrix, DMECM: decellularized meniscus extracellular matrix.

4.3.2. Electrospinning

Electrospinning is a technique capable of producing micro- and nanoscale fibers from polymers and composite materials, with tunable diameter, porosity, surface morphology, and fiber alignment. Electrospinning techniques can be employed to simulate the natural meniscus, producing porous composite scaffolds that enhance the anisotropy and heterogeneity of meniscal constructs [157,171,187]. Electrospinning supports that the incorporation of DMECM into synthetic nanofibers increased hydrophilicity of the scaffold, leading to enhanced meniscus cell spreading, proliferation, and fibrochondrogenic gene expression [142]. Gao S et al. developed a meniscal implant composed of a two-layer DMECM sponge and a three-layer electrospun DMECM/PCL fiber membrane, which exhibited a fivefold increase in biomechanical strength compared to the standalone DMECM scaffold and demonstrated superior moldability and good resistance to suture (Fig. 6b) [171]. Shimomura K et al. sutured with either an electrospun nanofibrous scaffold (PCL/PEO) combined with a TEC derived from SMSCs, to repair meniscal ring defects, thereby preventing meniscal extrusion (Fig. 6c) [157]. Electrospinning necessitates attention to several critical issues: the toxicity of solutes in the electrospinning solution, the crosslinking conditions, the type and source of enhancement factors, the integration between biomaterials, and the biomechanical functionality [[188], [189], [190]]. In order to optimize the limitation of toxic organic solvents in the preparation of spin solution, Xia B et al. tested two common collagen crosslinkers, glutamate aldehyde and kinipin [142]. The cross-linking of DECM/poly(ɛ-caprolactone) nanofiber in glutamate aldehyde and kinipin groups had considerable effects in terms of morphology and strength, collagen retention, surface wettability, and promotion of cell expansion and proliferation. The transcriptional activation rate of AC-H3K9 and POL-II in the kinipin group was higher than that in the kinipin group [142].

4.3.3. Three-dimensional printing

3D printing has become the predominant trend in developing meniscal replacement implants. 3D bioprinting includes nozzle-based and photopolymerization methods. Nozzle-based printing allows for creating customized tissues with interchangeable print heads for different bioinks but is limited by ink viscosity [143]. Photopolymerization provides high resolution and precision, minimizes contamination risks, and overcomes nozzle and viscosity limitations, though it is more expensive [191,192]. A detailed comparison of 3D printing methods is provided in Table 3.

3D printing mimics the natural collagen fiber arrangement within the meniscus, enhancing anisotropy, enabling load-bearing capacity and maintaining structurally sound mechanical properties. Lu J et al. employed PVA/DECM printing to fabricate a meniscus model, achieving a Young's modulus of 0.49 MPa, a compressive modulus of 2.9 MPa, the capability to recover 90% of plastic deformation, and the ability to withstand 80% compression without rupture [164]. Ma H et al. employed printing to fabricate PCL-Fib composite gradient scaffolds, which enhanced the compressive modulus and tensile modulus (Fig. 7a) [169]. The scaffolds also exhibited a high porosity, facilitating nutrient exchange. Du M et al. present a unique gradient-sized diamond-pored microstructure through dual-stage temperature control three-dimensional printing system based on the high M_w poly(ε-caprolactone) (Fig. 7b) [193]. Biologically, the unique gradient microtopology allows the seeded MSCs with spatially heterogeneous differentiation, triggering gradient transition of the extracellular matrix from the inside out. 3D printing has enabled a structural transformation of the meniscal scaffold, making it more anisotropic and thus closer to the natural structure of the meniscus. The biomimetic structure of the meniscus enhances the mechanical properties of the scaffold and ensures even load distribution, thereby avoiding stress concentration.

Fig. 7.

(a) The biomechanics of the composite scaffold (PCL-Fib) and the results of animal experiments [169]. (b) The biomechanics of the composite scaffold (the high Mw poly(ε-caprolactone)) and the results of animal experiments [193]. (c) Protein-spatiotemporal partition releasing gradient porous scaffolds and anti-inflammatory and antioxidant regulation remodel tissue engineered anisotropic meniscus [16]. (d) The biomechanics of the PSM-Mg scaffold and the results of animal experiments [194]. PCL: polycaprolactone, Fib: fibrin, TEM: tissue-engineered meniscus, USSP: the uniform square structured polycaprolactone scaffold was 215 μm, USDP: the polycaprolactone scaffolds with uniform diamond -structured followed the rhombic short diagonal 158 μm for printing, GSDP: the short diagonal of the gradient diamond structured polycaprolactone scaffold was 150 μm-350 μm from inside to outside, PCL@tetra-PEG: polylactone/4-arm poly(ethylene glycol) hydrogel, SA: sodium alginate, BGNs: bioactive glass nanospheres, Mg-BGNs: magnesium-containing bioactive glass nanospheres, PSM: polycaprolactone/sodium alginate scaffold incorporated with bioactive glass nanospheres, PSM-Mg: polycaprolactone/sodium alginate scaffold incorporated with magnesium-containing bioactive.

3D printing has also produced gradient porous structures, where the pore size influences the expression of collagen genes, promoting tissue growth heterogeneity [[15], [16], [17]]. Study have shown that PCL fibers with an inter-chain spacing of 100 μm yield the highest initial cell proliferation and exhibit the greatest percentage of orderly collagen alignment [195], resulting in tissues with higher elastic modulus at 4 weeks [196]. Xu B et al. also discovered that a meniscal scaffold made of PCL with a molecular weight of 60 kDa is more suitable for the growth of MSCs [16]. Recently, some studies have improved the microenvironment for meniscus regeneration and promoted its recovery by loading anti-inflammatory factors onto scaffolds. Xu B et al. developed a PCL@tetra-PEG meniscal scaffold loaded with the Ac2-26 peptide and growth factors CTGF and TGF-β3 for spatiotemporal partition release (Fig. 7c) [16]. Ac2-26 reduces inflammation and shifts macrophages from the M1 to the M2 phenotype, enhancing chondrocyte differentiation under inflammatory conditions. CTGF and TGF-β3 promote stem cell differentiation and collagen synthesis. Li H et al. fabricated PCL scaffolds incorporating Mg-BGNs, which effectively reduce inflammation and promote fibrocartilage formation by activating the TRPM7 and PPARγ/NF-κB pathways (Fig. 7d) [194]. Microenvironmental homeostasis is a critical factor influencing regenerative capacity and an indispensable focus in meniscal repair.

4.4. Meniscal tissue engineering: lessons from laboratory advances

Table 2 summarizes the application strategies of natural and synthetic polymers in tissue engineering, providing an intuitive display of material characteristics and mechanical performance. Combining the discussion of this section, personalized tissue engineering products may be tailored by evaluating the respective advantages of cells, materials, and manufacturing processes to address meniscal injuries of varying classification and severities. For instance, for minor injuries or degeneration, materials with superior biocompatibility but moderate mechanical strength can be selected as carrier platforms for stem cells or bioactive factors, preferably in injectable formulations. In contrast, for medium to large-scale injuries accompanied by biomechanical alterations, materials with higher mechanical strength should be chosen. These can be combined with electrospinning or 3D printing technologies according to specific requirements to mimic the anisotropic fibrous structure of native meniscus. Attention must be paid simultaneously to the integration between the implant and surrounding tissues, the stability of fixation, the regulation and balance of the microenvironment, and the relationship between scaffold degradation and tissue regeneration. These aspects present both broad prospects and challenges that we must address.

5. Future perspectives and translation

Translating effective tissue engineering research outcomes into clinical products, achieving painless knee joints, enabling patients to confidently return to work and sports, and reducing or eliminating recurrence represent common goals shared by patients, doctors, and researchers. Bridging the gap between clinical and laboratory is crucial for applying scientific findings to real-world treatments. Numerous challenges remain in translating research outcomes into clinical practice. We will discuss the prospects and challenges of translating research into practical applications from the perspectives of animal models, microenvironmental homeostasis, stem cell strategies, and manufacturing technologies.

5.1. Establishment of meniscus injury models

Animal models of meniscal injury are essential for translating tissue engineering strategies into clinical practice. Commonly used animal models include the perforation model, the vertical longitudinal tear model, and the partial or total resection model. Currently, no single model perfectly replicates human pathology, but careful selection based on research goals, species-specific anatomy, biomechanics, and healing potential improves clinical relevance. Researchers should consider multiple factors, including age matching, skeletal maturity, structural similarity, consistency of injury mechanisms, uniformity of treatment protocols, and standardized outcome assessments, when selecting the most appropriate animal model and conducting animal experiments consistent with clinical practice. Peng X et al. have provided a detailed review of animal models for meniscal injury that can serve as a reference [197].

5.2. Microenvironmental homeostasis

The homeostasis of the knee joint microenvironment is crucial for meniscal injury repair. It can prevent age-related degenerative changes and enhance the repair rate of traumatic tears. Potential approaches to restoring microenvironmental homeostasis include: (1) shifting macrophages from M1 to M2 phenotypes using small molecules, ions, or exosomes; (2) normalizing vascular growth to reduce inflammation and prevent excessive angiogenesis; (3) applying tissue engineering techniques to develop spatiotemporally controlled delivery systems that enable on-demand regulation of the microenvironment through intelligent platforms.

5.3. Stem cell strategy

MSCs have emerged as a promising therapeutic approach in regenerative medicine, primarily through their chondrogenic differentiation potential, immunomodulatory and anti-inflammatory properties, and paracrine functions mediated by exosomes. However, challenges such as variability between individuals, lack of standardized protocols, insufficient long-term data, and high costs hinder their widespread adoption. To achieve broader clinical application, it is necessary to ensure consistent therapeutic outcomes across different sources and cell batches, establish accepted treatment guidelines (specifying the optimal cell type, dose, injection frequency, or target patient population), conduct long-term follow-up studies, and reduce healthcare costs.

5.4. Materials and manufacturing technologies

We expect to use biomaterials and advanced manufacturing techniques to develop tissue-engineered products for meniscal repair or to address the limitations of existing products. Specific strategies such as: (1) constructing smart delivery platforms that remodel the meniscal microenvironment to inhibit degeneration or promote healing of meniscal tears; (2) 3D-printing biological scaffolds with biomechanical properties equivalent to those of the native meniscus to enable in situ tissue regeneration; and (3) developing simpler suturing or fixation systems to reduce the learning curve for junior surgeons. To achieve clinical translation of a meniscus scaffold, we may need to consider the following factors: assessment of the long-term safety of implantable materials, product stability issues arising from batch-to-batch material variations, the degree of alignment between material design and clinical practicality, and cost controllability.

6. Summary

The review elucidates the critical role of the meniscus structure, indicating that material design for 3D bionic structures will be the key trend from clinical treatment to laboratory research, with regenerative medicine demonstrating unique appeal. Further research on meniscal transformation should consider improving surgical accessibility, shortening the learning curve for surgeons, and reducing medical expenditures. It is hoped that future medical advancements will provide both physicians and patients with a broader array of choices.

Author contributions

D.W.: Conceptualization, Funding acquisition, Project Administration, Resources, Supervision, Writing-review and editing. H.L.: Conceptualization, Formal analysis, Methodology, Supervision, Writing-review and editing. S.L.: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing-original draft. Final approval: all authors.

Declaration of generative AI in scientific writing

During the preparation of this manuscript, the authors used DeepSeek solely to improve the clarity, fluency, and readability of the language. No scientific ideas, interpretations, data analyses, or conceptual content were generated by AI. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

Funding statement

This work was supported by National Natural Science Foundation of China (22575114), Shenzhen Science and Technology Program (KQTD20200820113012029 and KJZD20230923114612025), and Guangdong Provincial Key Laboratory of Advanced Biomaterials (2022B1212010003).

Conflict of interest

All authors declare that there are no competing interests.